| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Advanced Hepatocellular Carcinoma (HCC) without prior systemic therapy |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10073071 |
| E.1.2 | Term | Hepatocellular carcinoma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To determine and compare the overall survival of patients with advanced HCC without prior systemic therapy, treated with Pexa-Vec followed by sorafenib (Arm A) versus sorafenib (Arm B) |
|
| E.2.2 | Secondary objectives of the trial |
• Response based on central assessments using mRECIST for HCC for the following endpoints:
- TTP
- PFS
- ORR
- DCR
• Safety profiles of the 2 treatment arms
• TSP of the 2 treatment arms
• QoL of the 2 treatment arms
Exploratory Objectives:
• Response based on both local and central assessments using RECIST 1.1 for the following endpoints:
TTP
PFS
ORR
DCR
• Effect of treatment for both arms on the following endpoints:
- TIR and DoR
- Tumor size over time
- Efficacy in patient subgroups
- Overall survival, PFS, TTP in patients subdivided according to the presence or not of an objective response
• Changes in clinical laboratory parameters
• Overall survival by reference to the date of introduction of sorafenib
• Effects of Pexa-Vec on the immune response and biomarkers of response
• Cost-effectiveness of Pexa-Vec followed by sorafenib versus sorafenib alone |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Male or female patients, age ≥18 years old
2. Histological/cytological diagnosis of primary HCC
3. Advanced stage HCC (Barcelona Clinic Liver Cancer [BCLC] Stage C or B per American Association for the Study of Liver Disease [AASLD] guidelines) eligible for systemic therapy excluding cholangiocarcinoma, hepatocholangiocarcinoma, fibrolamellar carcinoma and hepatoblastoma
4. Tumor status (as determined by radiology evaluation): At least one measurable viable tumor in the liver, ≥1 cm longest diameter (LD), using a dynamic imaging technique (arterial phase of triphasic computerized tomography [CT] scan, or dynamic contrast-enhanced magnetic resonance imaging [MRI]), and injectable under imaging-guidance (CT and/or ultrasound)
5. At least one tumor that has not received prior local-regional treatment, or that has exhibited >25% increase in viable tumor size since prior local-regional treatment
6. Child-Pugh Class A
7. Performance status 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) scale
8. Adequate hematological, hepatic, and renal function:
a. Hemoglobin ≥9 g/dL
b. Platelet count ≥75 x 109/L
c. International normalized ratio (INR) ≤1.7
d. White blood cell (WBC) count ≥2 x 109/L
e. Absolute neutrophil count (ANC) ≥1 x 109/L
f. Albumin ≥2.8 g/dL, total bilirubin ≤3.0 mg/dL (51.3 μmol/L); alanine aminotransferase (ALT), aspartate transaminase (AST) ≤5 times upper limit of normal (ULN)
g. Serum chemistries sodium, potassium, and calcium within normal limits (WNL) or Grade 1
h. Serum creatinine <2.0 mg/dL or creatinine clearance >60 mL/min according to Cockroft-Gault formula
9. For patients who are sexually active: willing to use adequate barrier contraception method for at least 6 weeks after each treatment of Pexa-Vec, during sorafenib treatment, and for 2 weeks after sorafenib discontinuation
10. Life expectancy of at least 3 months
11. Written informed consent |
|
| E.4 | Principal exclusion criteria |
1. Major surgery within 4 weeks of study treatments (minor surgical procedures are allowed e.g., intravascular access line or Port-a-Cath®)
2. Local-regional therapy of HCC within 4 weeks prior to randomization
3. Histological diagnosis of cholangiocarcinoma, hepatocholangiocarcinoma, fibrolamellar carcinoma and hepatoblastoma
4. History of moderate or severe ascites, bleeding esophageal varices, hepatic encephalopathy or pleural effusions related to liver insufficiency within 6 months of screening
5. Bulky disease patients - tumors encompassing >50% of the liver volume and / or inferior vena cava invasion
6. Known significant immunodeficiency due to underlying illness and/or immune-suppressive medication including high-dose corticosteroids
7. Ongoing severe inflammatory skin condition requiring medical treatment
8. History of severe eczema requiring medical treatment
9. Tumor(s) invading a major vascular structure (e.g., carotid artery) or other key
anatomical structure (e.g., pulmonary airway) in the event of post-injection tumor swelling and/or necrosis (hepatic and portal vein involvement allowed)
10. Clinically significant and/or rapidly accumulating ascites, pericardial and/or pleural effusions. Mild ascites that does not preclude safe IT injection of Pexa-Vec is allowed at the discretion of the treating physician.
11. Symptomatic cardiovascular disease, including but not limited to significant coronary artery disease (e.g., requiring angioplasty or stenting) or congestive heart failure within the preceding 12 months
12. Current or past history of cardiovascular disease (e.g.. past history of myocardial infarction, ischemic cardiomyopathy) unless cardiology consultation and clearance has been obtained for study participation
13. Medical conditions, per the investigator’s judgment, that predispose the patient to untoward medical risk in the event of volume loading (e.g., intravenous [IV] fluid bolus infusion), tachycardia, or hypotension during or following treatment with Pexa-Vec
14. Viable central nervous system malignancy (history of completely resected or irradiated brain metastases allowed)
15. Prior systemic therapy for HCC
16. Known contraindications to sorafenib according to the drug prescribing information and/or severe hypersensitivity to sorafenib or any other component of sorafenib, or known intolerance to sorafenib
17. Other medical condition or laboratory abnormality or active infection that in the judgment of the Principal Investigator may increase the risk associated with study participation or may interfere with interpretation of study results and/or otherwise make the patient inappropriate for entry into this study
18. Hepatitis C virus therapy including interferon/pegylated interferon or ribavirin that cannot be discontinued within 14 days prior to any Pexa-Vec injection.
19. No prior malignancy except for the following: adequately treated basal or squamous cell skin cancer, in situ cervical cancer, adequately treated cancer from which the patient has been disease-free for at least 3 years
20. Significant bleeding event within the last 12 months that places the patient at risk for intrahepatic IT injection procedure based on Investigator assessment
21. Anticoagulant or anti-platelet medication that cannot be interrupted prior to Pexa-Vec IT injections, including:
• Aspirin that cannot be discontinued for 7 days prior to Pexa-Vec IT injections
• Coumadin that cannot be discontinued for 7 days prior to Pexa-Vec IT injections
• Low molecular weight heparin (LMWH) that cannot be discontinued >24 hours prior to Pexa-Vec IT injections
• Unfractionated heparin (UFH) that cannot be discontinued >4 hours prior to Pexa-Vec IT injection
• Oral direct thrombin inhibitor (dabigatran) or direct Factor Xa inhibitor (rivaroxaban, apixiban, and endoxaban) that cannot be discontinued for 4 days prior to Pexa-Vec IT injection
22. Inability to suspend treatment with anti-hypertensive medication for 48 hours prior to and 48 hours after each Pexa-Vec injection.
23. Any prior or planned organ transplant (e.g., liver transplant)
24. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation. Childbearing potential patients with a positive hCG laboratory test (>10 mIU/mL) at screening and/or a urinary pregnancy test at Baseline will perform an ultrasound to confirm the pregnancy.
25. Patients who experienced a severe systemic reaction or side-effect as a result of a previous vaccination with vaccinia
26. Participation in a clinical study and treatment with an active IP within 4 weeks prior to randomization
27. Patient unable or unwilling to comply with the protocol requirements
28. Previous treatment with Pexa-Vec or other vaccinia vector based treatment
29. Pulse oximetry O2 saturation <90% at rest on room air |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Overall Survival: time from date of randomization to the date of death due to any cause. If a patient is not known to have died at the cut-off date for analysis, survival will be censored at the date of last contact. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Please refer to section 5.B.1 of the Protocol |
|
| E.5.2 | Secondary end point(s) |
Secondary Endpoints:
• Time to Progression (TTP): time from randomization to the date of first documented radiographic tumor progression; TTP does not include deaths. If a patient has not had a TTP event at the cut-off date for analysis, TTP will be censored at the date of last evaluable tumor assessment before the cut-off.
• Progression Free Survival (PFS): time from randomization to the date of first documented radiographic tumor progression or death due to any cause, whichever occurs first. If a patient has not had a PFS event at the cut-off date for analysis, PFS will be censored at the date of last evaluable tumor assessment before the cut-off.
• Overall response rate (ORR): proportion of patients whose best overall response during their participation in the study is either CR or PR. The best overall response is the best response recorded from the randomization until disease progression.
• Disease control rate (DCR): proportion of patients whose best overall response during their participation in the study is either CR, PR, or stable disease (SD).
• Safety: assessed by the NCI CTCAE (version 4.03). Incidence of AEs and SAEs will be reported.
• Time to Symptomatic Progression (TSP): time from randomization until the first documented event of symptomatic progression defined as a decrease of 4 points or more from baseline in the FHSI-8 questionnaire (sub-part of the FACT-Hep questionnaire) or a decrease in performance status to 4, or death.
• Changes in the QoL assessed by changes in the FACT-Hep and EQ5D-3L questionnaires.
Exploratory Endpoints:
• TTP, PFS, ORR, and DCR as described above will also be assessed centrally.
• Duration of overall Response (DoR): applies only to patients whose best overall response is CR or PR. The start date is the date of first documented response (CR or PR) and the end date is the date of first documented disease progression or the date of death due to underlying cancer.
• Time to Initial Response (TIR): the start date is the date of randomization and the end date is the date of first documented response (CR or PR).
• Relative change of tumor size over time. Baseline tumor size is defined as the sum of the longest diameters for all target lesions as identified during screening.
• Changes in clinical laboratory parameters will be described including standard safety assessments, AFP levels, CD4 and CD8 counts (all assessed centrally).
• Additional immunology assays may be performed on archived samples to further assess the immune mechanisms involved and identify biomarkers of response. Pharmacoeconomy: information obtained from questionnaires collecting patient-level resource and service-use (Health Care Resource Utilization, Patient accommodation and Transport and EQ5D-3L questionnaires) will be analyzed. Detailed costs collected using data in eCRF, hospital invoices and pharmacy worksheet data will also be used as
information for pharmacoeconomy analyses. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Please refer to section 5.B.2 and 5.B.3 of the Protocol |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | Yes |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Quality of Life, Biomarker analysis |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 9 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 40 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Canada |
| China |
| France |
| Germany |
| Hong Kong |
| Israel |
| Italy |
| Korea, Republic of |
| New Zealand |
| Poland |
| Portugal |
| Singapore |
| Taiwan |
| Thailand |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 10 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
Print
